Antibacterial resistance has increased alarmingly in the recent years resulting in bacterial strains against which currently available antimicrobial agents are ineffective. In particular, Gram positive bacteria are presenting a formidable treatment problem. Methicillin Resistant Staphylococcus aureus (MRSA), Vancomycin Resistant Enterococci (VRE) and Glycopeptide Resistant Staphylococcus aureus (GRSA) are no longer objects of scientific curiosity but a life threatening proposition that is confronting physicians all over the world. The ‘super-bugs’ are here to stay and in addition to the several measures to control the spread of drug resistance, a concerted effort is still needed to develop new antibiotics to control life threatening bacterial infections. This growing multidrug resistance has recently rekindled interest in the search for new structural class of antibiotics that kill or inhibit the growth of these bacteria. See, Chemical Reviews, “Antibiotic Resistance”, 105 (2), February 2005.
Oxazolidinones are a class of antibacterial agents with a unique mechanism of inhibiting bacterial protein synthesis. They inhibit the formation of ribosomal initiation complex involving 30S and 50S ribosomes leading to prevention of initiation complex formation at the stage of protein synthesis. Due to their unique mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
Several patent publications disclose oxazolidinones as antimicrobial agents. For example, PCT publications bearing numbers WO 93/09103, WO 00/29396, WO 01/94342, WO 02/81469, WO 02/81470, WO 02/02095W0 03/072553, WO 03/006447, WO 03/07870, WO 03/08389, WO 03/97059, WO 04/056817, WO 04/056818, WO 04/14392, WO 04/009587, WO 04/018439A1, WO 05/058886, WO 05/082897, WO 05/116024, WO 05/116021, WO 05/082900, WO 05/003087, WO 06/043121 and US patents having numbers U.S. Pat. Nos. 6,689,779, 5,565,571, 5,801,246, 5,756,732, 5,654,435 and 5,654,428 disclose oxazolidinone compounds having antibacterial activity and useful as antimicrobial agents.
Some recent publications such as WO 07/114326, US 07/0155798, WO 07/040326, WO 07/095784, WO 07/000432, WO 07/004037 and WO 07/093904 disclose phenyl oxazolidinone derivatives as antibacterial agents. WO 06/109056, WO 06/035283, WO 03/072553, WO 03/064415 disclose heterobicyclic substituted phenyl oxazolidinones as antibacterial agents. WO 96/35691 and WO 00/073301 disclose bicyclic oxazolidinones as antibacterial agents. WO 02/064547 discloses pyridoarylphenyl oxazolidinones as antibacterial agents. WO 04/033451, WO 04/089943, WO 05/005422 and WO 05/005399 disclose bicyclo[3.1.0]hexyl-phenyl-oxazolidinone derivatives useful for treating bacterial infections. PCT publication WO 07/082910 discloses dicarbonyl compounds having antibacterial activity. A recent Chinese patent application CN 101434584 discloses phenyl oxazolidinones with glycinyl substitutions having antibacterial activity.
Linezolid (sold under the trade name Zyvox®), the first oxazolidinone to receive regulatory approval, has become an important clinical option in the treatment of serious Gram-positive bacterial infections, including those caused by multidrug resistant pathogens such as MRSA and VRE (see WO 95/07272). Inspite of its high potential as an antibiotic and its unique mode of action, no other molecule from oxazolidinone class, except for linezolid, could make it to the clinic. Moreover, development of resistance to an antibiotic is inevitable, and linezolid has been no exception. (See, Mutnick, A. H.; Enne, V.; Jones, R. N. Ann. Pharmacother., 2003, 37, 769-774). Further, due to myelosuppression, linezolid is not suitable for long duration therapy, although there are cases where patients receiving linezolid for more than two years are without serious side effects. (See, Hutchinson, D. K. Expert Opin. Ther. Patents 2004, 14, 1309-1328). Linezolid and its analogs (first generation oxazolidinones) are generally limited in their antimicrobial spectrum to Gram-positive pathogens only. An expanded spectrum and enhanced potency of newer second generation oxazolidinones with activity against Gram-negative pathogens could expand the utility of this class beyond the hospital setting into the treatment of community acquired infections. Thus, there is an ongoing need to develop more effective and safe compounds. The compounds of the present invention are novel, none of them having been previously reported in the prior art. The novel compounds of formula I according to the present invention possess improved efficacy, particularly enhanced activity against bacterial infections, appreciable bioavailability, reduced associated side effects, good solubility and can be made into formulations with ease.